9beta, 11beta-oxido-delta4-androstene-3, 17-dione



United tates Patent I 3,072,643 Patented Jan. 8, 1963 lice Thisapplication is a continuation-impart of my application Serial No.343,243, filed March 18, 1953, now abandoned, and a division of myapplication Serial No. 469,848, filed November 18, 1954.

The compound of this invention comprises a 95,11,8- oxido steroid of theandrostane series.

The steroid of this invention can be obtained by employing thecorresponding 9,8,11B-oxido steroid of the pregnane series as startingmaterial. The steroid of the pregnane series is converted to the9,8,11B-oxido steroid of the androstane series. The 9B,11 3oxido steroidof the androstane series can then be converted to the corresponding9a-halo, 11,8-hydroxy steroid. The latter may then be eitherdehalogenated to obtain the corresponding known 9-unsubstituted,llfi-hydroxy compounds, or oxidized to obtain the corresponding 9a-halo,ll-keto com pounds. The 9u-halo, ll-keto steroid of the androstaneseries can also be dehalogenated to produce the known 9-unsubstituted,ll-keto compounds.

The 95,11fl-oxido steroid of the pregnane series is prepared by themethod disclosed in my applications, Serial No. 343,243, and Serial No.417,489, filed March 18, 1953, now US. Patent No. 2,852,511, and March10, 1954, respectively, and an application of Fried and Herz, Serial No.434,672, filed June 4, 1954, now US. Patent No. 2,763,671.

The conversion of the 9,8,11/8-oxido steroid of the pregnane series intothe corresponding 9,8,11,8-oxido steroid of the androstane series isbest effected by reacting the former with an oxidizing agent in an acidsolution. Suitable oxidizing agents include compounds containing ahexavalent chromic ion (i.e. chromic oxide). Glacial acetic acid may beused as a suitable solvent. The reaction is most desirably conducted atroom temperature.

The 9,8,11,8-oxido steroid of the andrastane series is a very reactivecompound and is readily converted into the corresponding 9a-halo,llfl-hydroxy derivatives by treating with agents known to open an epoxyring under mild conditions. Thus, the ring can be split, inter alia, byhydrohalides such as hydrofluoric acid, hydrochloric acid, hydrobromicacid, and hydroiodic acid to form the corresponding9a-fluoro-11fl-hydroxy, 9a-chloro-11B-hydroxy, 9u-bromo-11fi-hydroxy and9ot-i0d0-1lB-hYCl1OXY deriva tives, respectively. These reactions arepreferably effected in an organic solvent, such as chloroform, at belowroom temperature.

The 9a-halo, IIB-hydroxy steroids of the androstane series can beoxidized to the corresponding 9u-halo, 11- keto derivatives by reactingthe former with an oxidizing agent such as chromic acid in glacialacetic acid.

The 9a-halo, llfl-hydroxy steroids of the androstane series, as well asthe 9oc-l'l8lO-11-k6t0 steroids of the androstane series, can bedehalogenated to the corresponding 9-unsubstituted, 11,8-hydroxy (orll-keto) steroid by treatment with zinc dust or chromous chloride in adilute lower alcohol (e.g. ethanol or methanol) or a lower fatty acid(eg acetic acid), respectively. By these processes, the novel 9a-halo,llfi-hydroxy (or ll-keto) steroids of the androstane series areconverted to the known 11;?- hydroxy (or ll-keto) steroids of theandrostane series. Thus, the 9a-halo-A -androstene-11fi-ol-3,17-dionesare converted to M-androstene-l1,B-ol-3,17-dione, a known 2 compound;andthe 9u-halo-A -androstene-3,11,17-triones, which can in turn be producedfrom the 9a-halo-A -androstene-llfi-ol-3,17-diones, are converted toandrenosterone (A -androstene-3,11,17-trione), a known compound havingestablished testoid activity.

The following examples are illustrative of the invention (alltemperatures being in centigrade):

EXAMPLE 1 9,8,1 1B-Oxido-M-androstene-SJ 7-di0ne from 918,115-oxido-M-pregnene-Z 7a,21-di0l-3,20-di0ne To a solution of 95,11B-oXido-A-pregnene-17a,21-diol- 3,20-dione (190 mg.) in 10 ml. of glacial aceticacid is added portionwise a solution of 190 mg. of chromic acid in 16.5ml. of glacial acetic acid. After one hour at room temperature 1 ml. ofalcohol is added and after an additional 10 minutes, the solution isevaporated to neardryness. The residue is distributed between 5 ml.Water and 20 ml. chloroform, and the resulting chloroform solutionextracted with water, dilute sodium bicarbonate and again with water.After drying over sodium sulfate, the chloroform is removed in vacuo andthe chloroform residue is crystallized from acetone-hexane affording93,11/3-oxido-A -androstene-3,17-dione having the follow ing properties:M.P. about 180l81 C.; +48 (c., 0.77 in chloroform);

A12; 242 my (e=15,200); will? 5.79 1, 6.0211, 6.06 11, 6.20;].

Analysis. Calculated for C I-T 0 (300.38); C, 75.97; H, 8.05. Found: C,75.71; H, 8.31.

96,11B-oxido-A -androstene-3,17-dione can then be converted to a9a-halo, 1lfl-hydroxy-A -androstene-3,17- dione by reacting the formerwith a hydrogen halide as illustrated by the following examples:

EXAMPLE 2 EXAMPLE 3 9a-Br0mo-A -Ana'rostene-SJ1,17-Trione From 9a-Bromo-M-Androslene-I 1 fl-Ol-3,1 7 -Di0ne 16.0 mg. of 9a-bromo-A-androstene-11 8-ol-3,17-dione is oxidized with 6.8 mg. of chromic acidas described in Example 1. The residue from the chloroform extract uponcrystallization from ethanol furnishes pure 9a-bromo-A-androstene-3,11,17-trione.

EXAMPLE 4 Andrenosterone From 9a-Br0m0-A -Andr0stene-3,11,17- Trione Toa solution of 10 mg. of 9u-bromo-A -androstene- 3,11,17-trione in 2 ml.of glacial acetic acid is added at steam bath temperature a total of 45mg. of zinc dust. Additions are made portion-wise and the reaction isinterrupted after 15 minutes. The residual zinc is removed bycentrifugation, and the acetic acid solution is evaporated to dryness invacuo. The residue is taken up in 3 ml. of water and 15 ml. ofchloroform. After separation of the resulting layers, the chloroformsolution is washed 4 with water, dilute sodium bicarbonate and againwith FOREIGN PATENTS water; and after drying over sodium sulfate thesolution 1 056 102 France Oct 21 1953 is evaporated to dryness. Theresidue after two crystalu lizations from 95% alcohol, yields crystals,M.P. 222- OTHER REFERENCES which do not depress thfi melting Point ofauthen- 5 Reich et al.: Helv. Chim. Acta, vol. 30, pages 329-334 ticandrenosterone. Furthermore, the infrared spectrum 1947 of this produceis identical with that of andrenosterone. Lieberman et 1 L Chem L 19pages 793..

I claim: 805 (1952). 95,1lfioxido'A4'andfostene'3,17"dine- Cole et al.:J. Am. Chem. Soc., vol. 74, pages 5571-5 References Cited in the file ofthis Patent 10 1 6 35 861 et al.: Helv. Chim. Acta, vol. 35, pages 295-UNITED STATES PATENTS 307 (1952). 2,602,769 Murray et al. July 8, 19522,734,897 Chemerda Feb. 14, 1956

